Evidence from animal studies suggests that the beta 3-adrenergic receptor plays a specific role in lipid homeostasis and thermogenesis. Recent reports have identified a common mutation (Trp64Arg) in the human beta 3-adrenergic receptor ((3-AR), and five separate investigations in different ethnic groups have found an association between this mutation and earlier onset of NIDDM, lower age- and gender-adjusted basal metabolic rate, and a propensity for massive weight gain. Mexican- Americans have high incidence and prevalence rates of NIDDM and obesity, and we have determined by genotyping 150 individuals from Houston and 772 individuals from Starr County, TX, that the (3-AR mutation is associated with obesity and increased cardiovascular risk in this ethnic group. Whether this mutation alters the function of the (3-AR in vivo is unknown, but if the mutated receptor is dysfunctional, then humans who express it would have a predictable metabolic phenotype. We hypothesize that this phenotype would be characterized by increased intraabdominal deposits of fat, blunted responses of net lipolysis to adrenergic stimulation and an exaggerated whole body proteolytic response to energy deficiency. A corollary of this hypothesis would be that the mutant receptor might accentuate the abnormalities of lipid, carbohydrate and protein metabolism characteristic of the diabetic state. Furthermore, homeostatic feedback responses between adipose tissue and the hypothalamus, mediated by the lipostatic hormone leptin and by the sympathetic nervous system, are likely to be disrupted. Sensitive techniques to quantify body fat mass in different compartments, and specific stable isotopic techniques to study metabolic parameters and radioimmunoassays for leptin are available to address these hypotheses.